scholarly journals Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease

Diabetologia ◽  
2019 ◽  
Vol 62 (7) ◽  
pp. 1154-1166 ◽  
Author(s):  
Hiddo J. L. Heerspink ◽  
Paul Perco ◽  
Skander Mulder ◽  
Johannes Leierer ◽  
Michael K. Hansen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mechanism Of Action ◽  
Diabetic Kidney Disease ◽  
Sglt2 Inhibitors ◽  
Potential Mechanism ◽  
Diabetic Kidney ◽  
Beneficial Effects

scholarly journals Dapagliflozin Ameliorates Diabetic Kidney Disease via Upregulating Crry and Alleviating Complement Over-activation in db/db Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Dong-Yuan Chang ◽  
Xiao-Qian Li ◽  
Min Chen ◽  
Ming-Hui Zhao
Keyword(s):  
Kidney Disease ◽  
Protective Effect ◽  
High Glucose ◽  
Diabetic Kidney Disease ◽  
Membrane Attack Complex ◽  
Sglt2 Inhibitors ◽  
Tubulointerstitial Injury ◽  
Diabetic Kidney ◽  
Proximal Tubular Epithelial Cells ◽  
Complement Regulator

Sodium-glucose cotransporter 2(SGLT2) inhibitors show prominent renal protective effect in diabetic kidney disease (DKD), anti-inflammatory effect being one of its key mechanisms. Over-activation of the complement system, a crucial part of innate immunity, plays an important role in DKD. We aimed to investigate the effect of SGLT2 inhibitors on alleviating complement over-activation in DKD. Db/db mice were randomly divided into two groups, with 7 mice in each group treated with dapagliflozin and vehicle respectively, and 7 mice in m/m mice group. Laboratory and renal pathological parameters were evaluated. Mouse proximal tubular epithelial cells (MPTECs) were cultured and treated with high glucose. Dapagliflozin and dimethyloxallyl glycine (DMOG) were added as conditional treatment. Dapagliflozin-treated db/db mice showed significantly lower urinary albumin than vehicle-treated ones. Besides typical glomerular and tubulointerstitial injury, both C3b and membrane attack complex (MAC) depositions were significantly attenuated in dapagliflozin-treated db/db mice. The expression of complement receptor type 1-related protein y (Crry), a key complement regulator which inhibits complement over-activation, was significantly upregulated by dapagliflozin. Dapagliflozin-mediated Crry upregulation was associated with inhibition of HIF-1α accumulation under high glucose. When HIF-1α expression was stabilized by DMOG, the protective effect of dapagliflozin via upregulating Crry was blocked. In conclusion, dapagliflozin could attenuate complement over-activation in diabetic mice via upregulating Crry, which is associated with the suppression of HIF-1α accumulation in MPTECs.

scholarly journals Exercise Ameliorates Diabetic Kidney Disease in Type 2 Diabetic Fatty Rats

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1754
Author(s):  
Itaru Monno ◽  
Yoshio Ogura ◽  
Jing Xu ◽  
Daisuke Koya ◽  
Munehiro Kitada
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Molecular Mechanisms ◽  
Kidney Injury ◽  
Male Rats ◽  
Fatty Acid Binding ◽  
Diabetic Kidney ◽  
Beneficial Effects ◽  
Type 2 Diabetic

Lifestyle improvement, including through exercise, has been recognized as an important mode of therapy for the suppression of diabetic kidney disease (DKD). However, the detailed molecular mechanisms by which exercise exerts beneficial effects in the suppression of DKD have not yet been fully elucidated. In this study, we investigate the effects of treadmill exercise training (TET) for 8 weeks (13 m/min, 30 min/day, 5 days/week) on kidney injuries of type 2 diabetic male rats with obesity (Wistar fatty (fa/fa) rats: WFRs) at 36 weeks of age. TET significantly suppressed the levels of albuminuria and urinary liver-type fatty-acid-binding protein (L-FABP), tubulointerstitial fibrosis, inflammation, and oxidative stress in the kidneys of WFRs. In addition, TET mitigated excessive apoptosis and restored autophagy in the renal cortex, as well as suppressed the development of morphological abnormalities in the mitochondria of proximal tubular cells, which were also accompanied by the restoration of AMP-activated kinase (AMPK) activity and suppression of the mechanistic target of rapamycin complex 1 (mTORC1). In conclusion, TET ameliorates diabetes-induced kidney injury in type 2 diabetic fatty rats.

Diabetic Kidney Disease

2019 ◽  
pp. 277-286
Author(s):  
John Cijiang He
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Early Stage ◽  
Pressure Control ◽  
Sglt2 Inhibitors ◽  
New Drugs ◽  
Diabetic Kidney ◽  
Mesangial Area ◽  
The World ◽  
Effective Drugs

Diabetic kidney disease (DKD) is the most common cause of ESRD in USA as well as in the world. The incidence and the prevalence of DKD have been increasing regardless of current intervention. The pathology of DKD is characterized by accumulation of extracellular matrix in GBM and mesangial area. The pathogenesis of DKD is multi-factorial including genetic, metabolic, and hemodynamic changes, which lead to activation of oxidative stress, inflammation, and fibrosis pathways in the diabetic kidney. Clinically, patients with DKD presents with glomerular hyperfiltration at early stage, then microalbuminuria, macroalbuminuria, and ESRD. However, the disease progression varies greatly among individual patients. Treatment of DKD is limited to hyperglycemic and blood pressure control and use of RAS blockade. Several new drugs such as SGLT2 inhibitors have been on phase 3 clinical trials but research is required to develop more effective drugs to treat DKD.

scholarly journals Targeting Inflammation in Diabetic Kidney Disease: Is There a Role for Pentoxifylline?

Kidney360 ◽  
2020 ◽  
Vol 1 (4) ◽  
pp. 292-299
Author(s):  
David J. Leehey
Keyword(s):  
Clinical Trials ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Standard Of Care ◽  
The United States ◽  
Sglt2 Inhibitors ◽  
Low Grade ◽  
Diabetic Kidney ◽  
Raas Blockade ◽  
Patients With Diabetes

Diabetic kidney disease (DKD) is the most common cause of ESKD in the United States and worldwide. Current treatment for DKD includes strict glycemic control and normalization of BP with renin-angiotensin-aldosterone system (RAAS) blockade. Although RAAS blockers slow progression of disease, they do not generally prevent ESKD and none of the studies with these agents in DKD included patients who were nonproteinuric, which make up an increasingly large percentage of patients with diabetes now seen in clinical practice. Recent studies with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown beneficial renal effects, and the benefits of SGLT2 inhibitors likely extend to patients who are nonproteinuric. However, there remains a need to develop new therapies for DKD, particularly in those patients with advanced disease. A role of chronic low-grade inflammation in microvascular complications in patients with diabetes has now been widely accepted. Large clinical trials are being carried out with experimental agents such as bardoxolone and selonsertib that target inflammation and oxidative stress. The Food and Drug Administration–approved, nonspecific phosphodiesterase inhibitor pentoxifylline (PTX) has been shown to have anti-inflammatory effects in both animal and human studies by inhibiting the production of proinflammatory cytokines. Small randomized clinical trials and meta-analyses indicate that PTX may have therapeutic benefits in DKD, raising the possibility that a clinically available drug may be able to be repurposed to treat this disease. A large, multicenter, randomized clinical trial to determine whether this agent can decrease time to ESKD or death is currently being conducted, but results will not be available for several years. At this time, the combination of RAAS blockade plus SGLT2 inhibition is considered standard of care for DKD, but it may be reasonable for clinicians to consider addition of PTX in patients whose disease continues to progress despite optimization of current standard-of-care therapies.

Sign in / Sign up

Export Citation Format

Share Document